My long-term objective is to understand how renal peritubular capillaries contribute to renal fibrosis, the final common pathway of all chronic kidney diseases. The proposed studies will investigate mechanisms that control peritubular capillary permeability, a major component of the inflammatory process leading to fibrosis, focusing on the adherens junction protein vascular endothelial cadherin (VE-cadherin) and its regulation by the angiogenic signaling molecule placental growth factor (PIGF). Preliminary data show that levels of VE-cadherin and PIGF are increased in the unilateral ureteral obstruction (UUO) model of chronic renal injury. Up-regulation of VE-cadherin may control fibrosis, whereas PIGF appears to be pro-fibrotic. The following aims will investigate how the expression and function of VE-cadherin change during chronic renal injury, test the hypothesis that altering VE-cadherin expression can modulate renal microvascular permeability and fibrosis, and determine whether PIGF acts by altering the function of VE-cadherin: (1) Delineate the changes in renal VE-cadherin expression, localization, and molecular interactions during chronic renal injury. UUO studies will investigate the changes in expression and cellular and subcellular localization of VE-cadherin by immunostaining and immuno-gold electron microscopy, and will also measure VE-cadherin phosphorylation and binding to associated proteins including catenins. (2) Test the hypothesis that up-regulation of VE- cadherin reduces the severity of renal fibrosis by limiting renal microvascular permeability and interstitial inflammation. UUO studies will use VE-cadherin heterozygote () mice and small interfering RNA (siRNA) to investigate how the level of VE-cadherin expression affects the progression of chronic renal injury. (3) Investigate the hypothesis that PIGF induces changes in VE-cadherin function that increase microvascular permeability and promote fibrosis. UUO studies using PIGF -/- mice will determine whether changes in VE- cadherin localization or phosphorylation are associated with modulation of renal fibrosis by PIGF. Cell culture studies will test whether PIGF directly affects VE-cadherin expression and function. This research has a large potential impact on public health, because one in nine Americans currently have chronic kidney disease, and 500,000 have end-stage disease and are on life-long therapy by dialysis or renal transplantation. Thus, alternative treatments for chronic kidney disease are urgently needed.